1. Field of the Invention,
The present invention relates to a device and to an in vitro method for modeling the iontophoretic sampling or delivery of substances through a membrane, such as the excised skin of a mammal. In another aspect, the present invention relates to a device and to a method for the iontophoretic delivery or sampling of substances through the intact skin of a living mammal. Specifically, the apparatus is a device which placed on the same side of intact skin has a positive electrode, a negative electrode and an electrically insulating material separating the electrodes. In still another aspect the present invention relates to an iontophoretic method of continuously monitoring the levels of bioactive materials in a subject and using a feedback mechanism to maintain effective levels.
2. Description of Related Art
Sampling-In-Vitro
C. C. Peck et al in Pharmacology Skin, Vol. 1, pp. 201-208 published by Karger, Basel 1987, discloses a method to determine in vitro the outward transdermal migration of theophylline using a passive transdermal collection system (TCS). The use of electrical enhancement of the migration is not disclosed.
R. R. Burnette et al in the Journal of Pharmaceutical Sciences, Vol. 75, No. 8, pp. 738-743, published in August 1986 using the standard diffusion cell discloses a comparison of the iontophoretic and passive in vitro transport of thyrotropin releasing hormone (TRH) across excised nude mouse skin. The results indicate that both charged and uncharged TRH fluxes across the excised tissue were greater than those obtained by passive diffusion alone.
In the standard (state of the art) arrangement for in vitro iontophoretic studies (See FIG. 6), the two halves of a diffusion cell are placed horizontally side by side so that the skin is located vertically between them, with its epidermal side facing one half and its inner side facing the other. The bioactive preparation and the active electrode are put in the xe2x80x9cepidermalxe2x80x9d half of the cell, and the other side of the cell contains the passive electrode in a conductive fluid.
This side-by-side arrangement has several drawbacks and limitations. Since the passive electrode is, in effect, placed xe2x80x9cinsidexe2x80x9d the skin, this configuration is not a good model of the in vivo case. The factors that influence such a non-physiological situation may not be those that are important in the clinical case. In addition, there are questions that cannot be investigated with a side-by-side configuration, such as the possibility of horizontal transport (i.e. within skin layers rather than vertically through the skin) and whether an iontophoretically driven drug is xe2x80x9cpulledxe2x80x9d back out of the skin by the passive electrode.
A state of the art iontophoretic drug delivery system, the Phoresor, is sold by Motion Control, Inc., 1290 West 2320 South; Suite A, Salt Lake City, Utah 84119.
Delivery-In-Vitro
In modeling studies, iontophoresis is useful to examine chemical transport of charged materials through a membrane, such as an excised skin sample. For instance, N. H. Bellantone, et al in the International Journal of Pharmaceutics, Vol. 30, pp. 63-72, published in 1986, disclose a standard state-of-the-art side-by-side diffusion cell design and electrode configuration for various systems utilized for iontophoresis of benzoic acid (as a model compound) (see FIG. 6). A number of limitations exist with the side-by-side cell design as is discussed further herein.
Delivery-In-Vivo
Iontophoresis is the electrically enhanced transport of charged substances usually bioactive materials. The procedure is a known means of transdermal drug delivery. For instance, in U.S. Pat. No. 4,141,359, by S. C. Jacobsen et al., which is incorporated herein by reference, disclose an improved iontophoresis device for the topical administration of ionic drugs or chemicals through epidermal tissue without mechanical penetration. The positive and negative electrodes are attached to the skin at separate locations. The ionic form of the drug is added to the appropriate electrode and is conducted into and through the epidermal tissue by means of direct current from a power source. A number of problems exist in this type of delivery, where the electrodes are separate.
Sampling-In-Vivo
There is a well-recognized and important need to sample and quantify bioactive substances in the body (typically, the blood). For example, it may be crucial to monitor the presence of a key endogenous biochemical for the purpose a disease diagnosis, or it may be essential to follow, and hence, optimize, the blood level of an administered drug during a chemotherapeutic regimen. Usually, the desired determination is achieved by analysis of a blood sample which is withdrawn invasively via an injected needle into a collection tube.
The passive transdermal collection of theobromine in vivo is also disclosed by C. C. Peck, et al. 1987, supra. No electrical current enhancement of the migration is disclosed.
No literature was found which describes a substantially noninvasive procedure for biomaterial sampling of the systemic circulation. It will require a unique application of iontophoresis to xe2x80x9cextractxe2x80x9d systemically circulating molecules into a collection device positioned on the skin or mucosal membrane surface. The present invention does not involve puncture of the skin nor of ally blood vessel.
Biosensing-In-Vivo
There exists a need to continuously or non-continuously monitor certain key biochemical parameters in hospitalized patients, and a need for a new class of medical devices to obtain real-time, on-line quantitation. A biosensor is a microelectronic device that utilizes a bioactive molecule as the sensing signal-transducing element.
K. W. Hunter, Jr., in Archives of Pathological Laboratory Medicine, Vol. III, pp. 633-636, published in July 1987, discloses in a general manner the range of devices and the physical properties which are examined. Hunter also includes a general diagram for a transdermal dosimeter. This reference does not provide needed additional specific information to create an operating biosensing-feedback-drug delivery system.
C. C. Peck et al in the Journal of Pharmacokinetics and Biopharmaceutics, Vol. 9, No. 1, pp. 41-58, published in 1981, discusses the use of continuous transepidermal drug collection (CTDC) in assessing drug in-take and pharmacokinetics. It was concluded that when back transfer is minimized, CTDC may be a useful tool to access the amount of drug exposure, etc., but offers little advantage over discrete sampling of other body fluids in the study of other aspects of drug disposition kinetics.
U.S. Patents of interest include: U.S. Pat. Nos. 4,329,999; 4,585,652; 4,708,716; 4,689,039; 4,702,732; 4,693,711; 4,717,378; 4,756,314; 4,699,146; 4 700,710; 4,706,680; 4,713,050; 4,721,111; 4,602,909; 4,595,011; 4,722,354; 4,722,726; 4,727,881; 4,731,049; 4,744,787; 4,747,819; 4,767,401.
Y. B. Bannon, European Patent Application Publication No. 252,732 (Jan. 13, 1988) to a transdermal drug delivery system is of general interest.
References of interest include:
W. Scharamm, et al., xe2x80x9cThe Commericalization of Biosensors,xe2x80x9d MDandGI, pp. 52-57, publised in November, 1987.
A. F. Turner, et al., xe2x80x9cDiabetes Mellitus: Biosensors for Research and Management,xe2x80x9d Biosensors, Vol. 1, pp. 85-115, published by Elsevier Applied Science Publishers, Ltd. England, 1985.
Y. Ikarlyaman, et al., Proc. Electrochem. Soc., 1987, 87-9 (Proc. Symp. Chem. Sens.) 378. CA 107-(22); 207350n.
P. H. S. Tso, et al. Anal Chem., 1987, 59 (19), 2339, CA 107(14); 1262448.
H. Wollenberger, et al., K. Anal. Lett., 1987, 20(5), 857, CA 107(9); 73551.
P. J. Conway, et al., D. A. Sens. Actuators, 1987, 11(4), 305, CA 107(5); 36151.
M. Mascini, et al., Clin. Chem., (Winston-Salem, N.C.) 1987, 33(4), 591 CA 107(5); 35851h.
I. Hanning, et al., Anal. Lett., 1988 19(3-4) 461, CA 105(6); 48993q.
M. Shirchirl, et al., Diabetes Care, 1986, 9(3), 298. CA 105(5): 38426t.
S. J. Churchouse, et al., Anal. Proc., (London) 1986, 2395), 146 CA 105(3) 21117v.
D. A. Gough, et al., Anal. Chem., 1985, 67(12), 2351. CA 103(15); 11925a.
C. Loo, et al., Chem. Eng. Sci., 1985, 40(5), 873 CA 103(5); 34337a.
All of the references and patents cited herein are incorporated by reference in their entirety.
It is desirable to have a device and a methodology to sample (or deliver) substances (charged or neutral) from (or to) a membrane (in vitro) or to sample (or deliver) substances (charged or neutral) from (or to) the intact skin (muscosa, etc.) of a living mammal. The present invention accomplishes these objectives.
In one aspect, the presnt invention relates to a method AAA for non-invasively determining the level of an inorganic or organic substance contained in the skin surface, underlying tissue or in the circulating blood of a living human being, comprising
(a) placing a collection reservoir of an electrically conducting medium in contact with the skin surface of the human being, wherein said collection reservoir is in electrical communication with the skin surface and a first electrode,
(b) placing a second collection reservoir and second electrode in communication with a separate area of the skin surface creating an electric circuit,
(c) creating between the first and second electrodes electrical current of ions of sufficient magnitude and duration to cause detectable levels of inorganic or organic substance and/or at least one of its metabolites to migrate from the skin surface, underlying tissue, or the circulating blood into the collection reservoir and electrode and the second collection reservoir and electrode, and
(d) analyzing the level of the collected extracted inorganic or organic substance or at least one of its metabolites in the collection reservoir or second collection reservoir.
In another aspect, method AAA further includes:
(e) correlating the level of the inorganic or organic substance or at least one of its metabolites in the skin surface, underlying tissue or blood circulation with the extracted levels of the inorganic or organic substance, at least one of its metabolites or combinations thereof, particularly wherein in step (e) the concentration level of the inorganic or organic substance in the skin surface, underlying tissue or in the circulating blood is correlated by comparison to a predetermined standard using extracted concentration of the inorganic or organic substance or at least one metabolite thereof in the collection reservoir, the second collection reservoir or the sum or the difference of the concentration levels of organic or inorganic substances or their metabolites or products or ratios thereof.
The present invention relates to a diffusion cell device for use in the electrically enhanced sampling of a substance from a membrane surface or the delivery of a substance into or through a membrane surface without mechanical penetration comprising
at least two electrically conducting permeable electrode means for contacting the membrane surface, and
means for electrically isolating each electrically conducting electrode means from each other,
wherein said electrode means are disposed in substantially a side-by-side relationship having sides extending and terminating in a substantially common face surface which contacts immediately adjacent portions of the same side of said membrane surface.
In another aspect, the present invention relates to an in vitro device for the removal or delivery of either ionized or unionized substances from a membrane sample without mechanical penetration, which device comprises:
(a) a positive electrode;
(b) a negative electrode, and
(c) electrical insulation between subpart (a) and (b), wherein the positive electrode, and the negative electrode, and electrical insulation are positioned on the same side of the membrane sample.
In another aspect, the present invention relates to a device for the removal of or delivery of ionized substances to a mammal through intact skin or mucosal membrane without mechanical penetration, which device comprises:
(a) a positive electrode,
(b) a negative electrode, and
(c) an electrically insulating material between subpart (a) and (b), wherein the positive electrode, negative electrode and insulating material are physically positioned so that each present a single common surface of the device for contact with the same side of the skin or mucosal membrane of the mammal.
In another aspect, the present invention relates to the use of iontophoresis to determine the level of a uncharged or charged molecule in a living mammal, and with the use of a feedback mechanism, administer appropriate levels of therapeutic substance by any number of available administration routes.
In another aspect the invention relates to the use of iontophoresis to enhance the collection of a charged or neutral substance from a membrane or the skin of a living mammal at one electrode followed by analysis of the concentration of the substance by gas chromatography (GC), mass spectrometry (MS), by high pressure liquid chromatography (HPLC), scintillation counting, and the like.